Here, TBC1D31 is identified as a novel Rab GTPase activating protein to catalyze GTP hydrolysis for Rab22A, which mediates endolysosomal trafficking and degradation of EGFR, and proposes TBC1D31 as a novel actionable target for HCC patients with 8q24.13 amplification. This evidence concerns the gene EGFR and hepatocellular carcinoma.